Magnetic Field Treatment Techniques

ABSTRACT

The invention involves enhancing brain function by stimulating the brain using magnetic fields. Applications of the new methods include improving the condition of individuals with cognitive disorders, such as depression, and studying the effects of neural stimulation using induced electric fields. These techniques can avoid deleterious effects of psychotropic pharmaceutical treatments, and provide a relatively safe, comfortable, inexpensive means of direct cranial stimulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 11/580,272, filed Oct. 12, 2006, which is acontinuation-in-part of and claims priority to U.S. patent applicationSer. No. 11/404,051, filed on Apr. 13, 2006, which is now U.S. Pat. No.7,282,021, which is a continuation application of U.S. patentapplication Ser. No. 10/452,947, filed on Jun. 2, 2003, which is nowU.S. Pat. No. 7,033,312, which is a continuation application of U.S.patent application Ser. No. 09/839,258, filed Apr. 20, 2001, which isnow U.S. Pat. No. 6,572,528. The disclosure of the prior applicationsare considered part of (and are incorporated by reference in) thedisclosure of this application.

TECHNICAL FIELD

This invention relates to magnetic stimulation techniques, and moreparticularly to neural stimulation using a magnetic field.

BACKGROUND

Repetitive transcranial magnetic stimulation (rTMS) has been used withthe goal of treating depression, see, e.g., George et al., The Journalof Neuropsychiatry and Clinical Neurosciences, 8:373, 1996; Kolbinger etal., Human Psychopharmacology, 10:305, 1995.

One example of an rTMS technique uses a figure-8 surface coil with loopsthat are 4 cm in diameter (Cadwell, Kennewick, Wash.). This coil isplaced next to the scalp, and is usually positioned to direct themagnetic field at the prefrontal cortex of the brain, see, e.g., Georgeet al., The Journal of Neuropsychiatry and Clinical Neurosciences,8:373, 1996. An electric current is run through the magnetic coil togenerate a magnetic field, specifically a sequence of single-cyclesinusoidal pulses where each pulse has a frequency of approximately 1800Hz (or about 560 microseconds per pulse). These pulses are delivered ata repetition rate of 1 to 20 Hz (i.e., one pulse every 0.05 to 1second), see, e.g., George et al, Biological Psychiatry, 48:962, 2000;Eschweiler et al, Psychiatry Research: Neuroimaging Section, 99:161,2000.

Some subjects have declined participation in rTMS studies due to paininduced in the scalp. In addition, seizures have been reported as aresult of rTMS treatment, see, George et al, Biological Psychiatry,48:962, 2000; Wasserman, Electroencephalography and ClinicalNeurophysiology 108:1, 1998.

SUMMARY

The invention concerns treating disorders using novel magnetic fieldtechniques. These techniques have generally been termed low-fieldmagnetic stimulation (LFMS) techniques. These magnetic field techniquesgenerally use low field strengths, high repetition rates, and relativelyuniform magnetic field gradients to improve brain function.

In one aspect of the present invention, a method of treatment involvesselecting a person who experiences symptoms of a psychotic disorder,such schizophrenia or a schizoaffective disorder, and subjecting theperson's head to a time-varying magnetic field which has been generatedto treat the symptoms of the psychotic disorder. The magnetic field thatis generated induces an electric field in air comprising a series ofelectric pulses, where the pulses have a duration less than about 10milliseconds, and where each pulse has a single polarity and the pulsesare separated by periods of substantially no electric field. This aspectof the invention can also be used to treat abuse or dependence on asubstance such as alcohol or nicotine. In addition, it can be used totreat other disorders such as attention deficit hyperactivity disorder,post-traumatic stress disorder, obsessive-compulsive disorder, bipolardisorder, panic disorder, and pain and movement disorders.

Advantages of this aspect of the invention include the following.Subjects with disorders may benefit from the new treatment by thelessening of the severity of the condition. Treatment techniques usingthis method can be administered inexpensively with relative safety andcomfort, and offer a substitute for or complement to treatment bymedication. Applications of the new methods include improving thecondition of individuals with disorders and studying the effects ofbrain stimulation using induced electric fields.

Embodiments of this (and other) aspects of the invention can include thefollowing features. The duration of each pulse in the sequence can beless than or equal to about 1 millisecond. Successive electric pulsescan have alternating polarity. The electric field in air can besubstantially unidirectional over at least a region of the brain, suchas an interior region of the brain, e.g., the prefrontal cortex. Theelectric field in air can be substantially spatially uniform (e.g., havea change in magnitude within 10% or 20%, or possibly larger) over atleast a region of the brain, such as an interior region of the brain,e.g., the prefrontal cortex. The magnetic field that creates thiselectric field can be a gradient magnetic field (i.e., a magnetic fieldone or more of whose x, y, or z direction components variesapproximately linearly in space). The effectiveness of the method oftreatment can be evaluated by evaluating the person for improvement ofsymptoms after subjecting the person to the magnetic field.

In another aspect of the present invention, a method of treating aperson who experiences symptoms of a psychotic disorder involvesgenerating a time-varying magnetic field, where the magnetic fieldinduces an electric field in air comprising a series of electric pulses.The series of pulses has a frequency of at least about 100 Hz, eachpulse has a single polarity, and the pulses are separated by periods ofsubstantially no electric field. Subjecting the person's head to thistime-varying magnetic field treats the symptoms of the psychoticdisorder, e.g., schizophrenia or a schizoaffective disorder. This aspectof the invention can also be used to treat abuse or dependence on asubstance such as alcohol or nicotine. In addition, it can be used totreat other disorders such as attention deficit hyperactivity disorder,post-traumatic stress disorder, obsessive-compulsive disorder, bipolardisorder, panic disorder, and pain and movement disorders. Inembodiments of this treatment protocol, the frequency of the series ofelectric pulses is about 1 kHz.

In another aspect of the invention, a method of treating a person whoexperiences symptoms of a psychotic disorder involves generating atime-varying magnetic field with a maximum strength of less than about500 G (e.g., 50 or 225 G), where the magnetic field induces an electricfield in air comprising a series of electric pulses. Each pulse has asingle polarity and the pulses are separated by periods of substantiallyno electric field. The person's head is subjected to the time-varyingmagnetic field to treat the symptoms of the psychotic disorder, e.g.,schizophrenia or a schizoaffective disorder. This aspect of theinvention can also be used to treat abuse or dependence on a substancesuch as alcohol or nicotine. In addition, it can be used to treat otherdisorders such as attention deficit hyperactivity disorder,post-traumatic stress disorder, obsessive-compulsive disorder, bipolardisorder, panic disorder, and pain and movement disorders. Inembodiments of this treatment protocol, the maximum magnetic fieldstrength is less than about 50 G (e.g., 10 G). In other embodiments, theelectric pulses have an amplitude less than about 10 V/m (e.g., 5 V/m).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram of a system and apparatus for administering thepresent magnetic field treatments.

FIG. 2 is an example of a magnetic field waveform used in the presentmagnetic field treatment methods.

FIG. 3 is an example of an electric field waveform induced using thepresent magnetic field treatment methods.

FIG. 4 is a table summarizing the effects of the present treatment.

FIG. 5 is a table summarizing the statistical significance of theeffects of the present treatment.

FIG. 6 is an example of a magnetic field waveform used in an example ofrepetitive transcranial magnetic stimulation.

FIG. 7 is a three-dimensional plot of a magnetic field used in anexample of repetitive transcranial magnetic stimulation.

FIG. 8 is an example of an electric field waveform induced using anexample of repetitive transcranial magnetic stimulation.

FIG. 9 is a contour plot of an electric field used in an example ofrepetitive transcranial magnetic stimulation.

FIG. 10 is a three-dimensional plot of an electric field used in anexample of repetitive transcranial magnetic stimulation.

FIG. 11 is a table comparing parameters for an exemplary repetitivetranscranial magnetic stimulation protocol to parameters for anexemplary protocol of present magnetic field treatment methods.

DETAILED DESCRIPTION Apparatuses and Systems

A device 10 according to the present invention is shown in FIG. 1. Thedevice 10 has a magnetic coil 12, an amplifier 14, and a waveformgenerator 16. The waveform generator 16 (e.g., a general-purposeprogrammable computer or a purpose-built electric circuit) provides anelectrical pulse sequence to the amplifier 14, which amplifies theelectrical signals and provides them to the magnetic coil 12.

The magnetic coil 12 produces a magnetic field in response to electricalsignals received from the amplifier 14. If the signals vary in time,then it also necessarily produces an electric field, and this electricfield is substantially uniform and unidirectional over the region inwhich the subject's brain is positioned. One way that this can beachieved is if the magnetic field has a spatial gradient that issubstantially uniform (i.e. the magnetic field strength of any onevector component of the magnetic field varies substantially linearlywith distance). The electric field for any coil configuration can beexpressed as the sum of several potential terms; including some relatedto the magnetic field. If the gradient of the magnetic field issubstantially uniform and unidirectional then inhomogeneity in theelectric field will be reduced, providing a substantially uniform andunidirectional electric field according to Maxwell's Equations(reference Jackson 1975). (Alternatively, a magnetic coil can be usedthat generates a substantially uniform and unidirectional gradientmagnetic field over only a region of interest of the brain, e.g., theleft prefrontal cortex.) Other magnetic configurations can be utilizedthat are consistent with a substantially uniform electric field asrequired by Maxwell's Equations. The magnetic coil 12 is large enough toaccommodate a subject's head, with a diameter of, e.g., about 35 cm (14in.).

When being treated with device 10, the subject 18 lays down on astandard patient gurney 20 with a head support 22, with his or her headpositioned inside the coil 12. An alternative would be to use a smallerdevice where only the top of the patient's head lies within the coil.

Other devices can also be used for administering the present treatmentmethod. For instance, a conventional magnetic resonance imagingapparatus can be used. Alternatively, instead of using a device such asdevice 10 that consists of separate components, the device can insteadintegrate one or more components, e.g., to make the device easilyportable. Alternatively or additionally, the magnetic coil can beincluded in a hat-like structure, and the waveform generator, amplifier,and power source (e.g., a battery) integrated into a control mechanismthat the subject carries or wears, i.e., on his or her subject's belt.The subject can self-administer the treatment, and the treatment can beapplied while the subject is lying down, standing, sitting, or inmotion. Alternatively or additionally, the control device can be pre-setto administer the treatment for specific periods at specific intervalsor continuously.

Methods

Prior to receiving treatment using device 10, a subject is selected as acandidate for enhancement of brain function. This selection is generallyperformed by medical professionals, e.g., because the subject has beendiagnosed as suffering a psychiatric disorder. Alternatively, a subjectcould self-select based on a perceived need or desire to enhance brainfunction. Selection can be based on either subjective or objectivecriteria, including, e.g., anxiety, moodiness, depression, lethargy,sleepiness, learning difficulties, memory impairments, attention deficithyperactivity disorder, post-traumatic stress disorder,obsessive-compulsive disorder, bipolar disorder, panic disorder, andpain and movement disorders.

To administer the treatment, the subject's head is positioned insidecoil 12, and subjected to a time-varying magnetic field. (Alternatively,the subject's entire body could be positioned inside a full-body coil,and subjected to a time-varying magnetic field.)

The magnetic pulse train used to generate the time-varying magneticfield is shown in FIG. 2. The pulse train comprises a sequence of pulsesdelivered at a high rate. As discussed in detail below, the magneticfield induces an electrical field in the subject's brain. Thiselectrical field can interact with neurons to cause cognitive effect. Inlight of this, the duration of each individual magnetic pulse isselected to be on the order of the refractory period of an axon, i.e.,on the order of several milliseconds, see, e.g., E. R Kandel et al.,Principles of Neural Science, 1991, which is incorporated by referenceherein. Thus, the pulse duration can be from on the order of 0.1milliseconds to 10 milliseconds (e.g., 0.25 milliseconds).

For example, each magnetic pulse has a trapezoidal shape, with 128microsecond ramp times (from zero to plateau) and 768 microsecondplateau times (for a total duration of 1.024 milliseconds). The pulsesalternate in polarity, and may be delivered in discrete pulse trains. Asingle pulse train comprises 512 successive pulses, and so lasts forabout a half-second. After a delay of about a second-and-a-half, thepulse train is repeated (giving one pulse train every two seconds), andthe treatment concludes after about six hundred repetitions (for a totaltreatment time of about 20 minutes). Alternatively, thesecond-and-a-half delay between successive pulse trains can beeliminated.

At the plateau of each trapezoidal pulse, the maximum magnetic fieldstrength is on the order of 5-10 G, with a magnetic field gradient of,e.g., 0.33 G/cm for some devices, 1.52 G/cm for other devices, and canbe substantially greater for still other devices. Pulse sequencesyielding maximum magnetic field strengths of up to about 500 G (e.g.,225 G), and maximum magnetic field gradients of up to about 25 G/cm(e.g., 13 G/cm), can alternatively be used.

These magnetic fields induce electric fields in the subject's brain. Thecharacteristics of these electric fields are defined by the magneticfield parameters according to Maxwell's equation: ∇×E(x, y, z, t)=−∂B(x,y, z, t)/∂t, where ∇×E is the curl of the electric field and

$\frac{\partial B}{\partial t}$

is the rate of change of the magnetic field over time. In Cartesiancoordinates, this equation becomes:

∂E _(x) /∂y−∂E _(y) /∂x=−∂B _(z) /∂t,

∂E _(y) /∂z−∂E _(z) /∂y=−∂B _(x) /∂t,

∂E _(z) /∂x−∂E _(x) /∂z=−∂B _(y) /∂t,

where the subscripts x, y, and z denote the component of the fieldsalong those respective axes, see, e.g., J. D. Jackson, ClassicalElectrodynamics, 1975, which is incorporated herein by reference.

These equations describe fields in free space (i.e., fields produced inthe absence of other material). When conductive matter, such as braintissue, is placed in the changing magnetic field, a charge distributionis also induced, resulting in an electric field. This electric fieldwill affect the overall electric field in the head. This chargedistribution can alter the free space electric field by up to about 50%,see Roth et al, Electroencephalography and Clinical Neurophysiology,81:47, 1991, which is incorporated herein by reference. The pattern ofthe effect of the charge distribution will depend on the shape andplacement of the subject's head.

Two local field distributions are of particular interest. In the first,the z-component (superior-inferior component) of the magnetic field hasa uniform gradient in the y-direction (anterior-posterior direction),and the y-component has a uniform gradient in the z-direction: (B_(x)=0,B_(y)=G(t)z, B_(z)=G(t)y), where G(t) is the value of the gradient. Inthis case, the electric field can generally be described by thefollowing equation (small additional corrective terms may be involved):(E_(x)=E₀(t)+½(∂G(t)/∂t)·(y²−z²), E_(y)=0, E_(y)=0, E_(z)=0), whereE₀(t) is a spatially constant field term that depends on the size of thecoil and, consequently, the extent of the magnetic field. The precedingfield description applies equally for the two other orientations, whichare obtained by replacement of x with y, y with z, and z with x or byreplacement of x with z, y with x and z with y, in both the vectorcomponents and coordinates. In addition, a given vector combination ofthese three field components, which forms an equivalent but rotatedfield, is also appropriate. Thus, one approach to applying the newtreatment techniques involves using a magnetic field that has a vectorcomponent with a gradient that is substantially uniform, e.g., to within10%, in value or direction over a relevant volume of the subject'sbrain, e.g., a 8 cm³ volume or the prefrontal cortex.

In another magnetic field distribution, the magnetic field is uniformover a local volume, which can be expressed as: (B_(x)=0, B_(y)=0,B_(z)=B(t)). The corresponding local electric field can generally bedescribed by the following equation (small additional corrective termsmay be involved): (E_(x)=E₀(t)−a(∂B(t)/∂t)·y,E_(y)=E₀(t)−(1−a)(∂B(t)/∂t)·y, E_(z)=0), where a is an arbitraryparameter determined by the details of coil winding.

In both situations, if E₀(t) is sufficiently large compared to∂G(t)/∂t·R² or ∂B(t)/∂t·R, where R is an effective radius of the volumeof interest, e.g., the radius of a subject's brain, then the localelectric field is substantially uniform. The preceding field descriptionapplies equally for other orientations and rotations.

An LFMS magnetic field can have the following spatial dependence: {rightarrow over (B)}(x, y, z)=G(y{circumflex over (z)}+zŷ), where G is thegradient magnetic field strength in Gauss/cm (e.g., 0.33 G/cm forcertain devices and 1.52 G/cm for other devices, as mentioned above) and“z hat” indicates field in the z direction. This field distribution isaccurate over the region of the head but may have a differentdistribution outside that region.

The induced electric field accompanying the LFMS magnetic field has thefollowing spatial dependence: {right arrow over (E)}(x,y,z)={dot over(A)}₀{circumflex over (x)}+½G(y²+z²){circumflex over (x)}, where “A₀dot” is time rate of change for the vector potential of the coil at thecenter of the active region and has the units of electric field (V/m)and “G dot” is time rate of change for the gradient magnetic field. “A₀”is a characteristic of the coil and current waveform, and determines theinduced electric field strength of the coil. “A₀ dot” can be, e.g., 0.7V/m for certain devices, 1.5 V/m for other devices, and substantiallyhigher for still other devices. The electric field for the LFMS coil issubstantially described by the first term, while the second termproduces an inhomogeneity in the volume. The LFMS electric fieldwaveform can be described by 5 parameters: pulse amplitude (V/m), pulseduration (μs), pulse frequency (Hz), repetition time (sec), totaltreatment time (min) and alternating sign of pulses (yes or no).Additionally, the electric field is characterized by a 6th parameter,the direction of the field. The preceding field description appliesequally for the two other orientations, which is obtained by replacementof x with y, y with z, and z with x or by replacement of x with z, ywith x and z with y, in both the vector components and coordinates. Inaddition, a given vector combination of these three field components,which forms an equivalent but rotated field, is also appropriate.

FIG. 3 shows the electric field waveform induced in the subject's brainwhen subjected to the magnetic field waveform shown in FIG. 2. Theelectric field waveform is a sequence of square pulses of alternatingpolarity. The pulses are monophasic, here meaning that each pulse has asingle polarity. Each pulse is separated from the neighboring pulses bya period of substantially no electric field. The width of each inducedelectric pulse corresponds to the ramping period for the magnetic fieldpulses, i.e., 256 microseconds. For the 1.8 G/cm magnetic field pulseamplitude, the electric field amplitude is approximately 1.4 V/m. Thiselectric field strength is approximately an order of magnitude less thanthe minimum peripheral nerve stimulation threshold of approximately 6-25V/m, see, e.g., J. P. Reilly, Medical and Biological Engineering andComputing, 27:101, 1989, thus providing an appropriate margin of safetyagainst causing pain or seizures in the patient.

Use of LFMS to Affect Brain Function

The use of LFMS to date indicates that LFMS affects brain function. LFMSmay affect brain function in several ways, with one mechanism being aneffect on white matter tracts in the brain. White matter effects couldresult from an enhancement of electrophysiological function in theneurons making up the white matter tracts. White matter structures suchas the corpus callosum may be especially sensitive to the LFMS electricfield. This enhancement could produce results directly by increasingwhite matter function in diseased or compromised neurons through amechanism similar to long-term potentiation in which neural thresholdsare reduced through electrochemical changes; it could also produceresults through immediate enhancement of white matter function incortical circuits that regulate mood and affect; and both of thesemethods could produce longer lasting effects in post-synaptic graymatter by enhancing cell growth. It is possible that pre-synapticinteraction could provide a basis for immediate mood effects, andpost-synaptic effects could provide effects associated with longer timesscales such as participation in second messenger systems leading tochanges in gene expression, neurotrophic responses and dendriticsprouting in the hippocampus see, E. J. Nestler et al., Neuron 34:13-25,2002; M. A. Smith M A et al., J Neurosci 15:1768-77, 1995. Inparticular, post-synaptic changes could affect deficits in Brain DerivedNeurotrophic Factor (BDNF) which regulates neural growth and dendtriticsprouting.

A number of disorders are associated with abnormalities in white mattertracts and BDNF deficits including mood disorders (e.g., bipolardisorder and late-life depression), psychotic disorders (e.g.,schizophrenia and other schizoaffective disorders), anxiety disorders(e.g., panic disorder, OCD, and PTSD), ADHD, and substance abuse anddependence. Some of these disorders share activation deficit patternswith depression, as measured by functional magnetic resonance imaging(fMRI) and positron emission tomography (PET). LFMS may treat thesedisorders and alleviate their symptoms.

LFMS could affect white matter directly, enhancing white matterfunction. During white matter enhancement such as occurs in long termpotentiation, the electric field induced during the LFMS exposure maycause the observed effects by directly affecting ion concentrations andother electrochemical signaling mechanisms within the neuron. The LFMSelectric field is about 1 V/m, of a magnitude that could affect theelectrochemical processes supporting neural signaling, see W. Irnich W,MAGMA 2:43-49, 1994; W. Wang et al., In Proceedings of Joint Meeting ofthe Society of Magnetic Resonance Third Scientific Meeting andExhibition and the European Society for Magnetic Resonance in Medicineand Biology, 19-25 Aug. 1995 (pp. 73), 1995 [Nice, France: SMR/ESMRMB].Changes in ion concentration near receptors or ion channels that arecaused by the fields from LFMS could provide an effect similar to longterm potentiation (LTP). This effect might be strongest in white mattertracts that particularly align with the electromagnetic field. Inparticular LTP has been studied for involvement in animal models ofstress and depression, see M. Popoli et al., Bipolar Disord 4:166-82,2002; E. Tsvetkov et al., Neuron 41:139-51, 2004, and has been seen instudies in animal models of depression, see Y. Levkovitz et al.,Neuropsychopharmacology 24:608-16, 2001; M. Ogiue-Ikeda et al., BrainRes 993:222-6, 2003.

The direct action of LFMS on white matter could affect the function ofnetworks of neurons in cortical areas. These effects could result fromwidespread interaction with neurons that participate in a “neuralcircuit” that controls a high order of brain function. Neural circuitshave been implicated in models of depression through patterns ofactivation using fMRI and PET, see H. S. Mayberg, Br Med Bull65:193-207, 2003.

LFMS could also enhance brain function post-synaptically by changing thefunction of cells located at the synapses at the termination of directlyaffected neurons. Post-synaptic effects include an increase in braingrowth and dendritic sprouting, which reverse the degenerative effectsof various diseases. The hippocampus is a brain structure that has beenstudied as an area that could provide a post-synaptic site for theeffects of treatment. Depression, anxiety disorders, schizophrenia andsubstance abuse disorders are associated with neuronal degeneration inthe hippocampus and reductions in dendritic branching, see R. S. Dumanet al., Arch Gen Psychiatry 54:597-606, 1997; A. V. Kalueff et al.,Science 312:1598-9, 2006; G. Shoval. & A. Weizman, EurNeuropsychopharmacol. 15(3):319-29, 2005; P. H. Janak, Alcohol Clin ExpRes., 30(2):214-21, 2006. Successful treatment of these disordersincreases BDNF expression in the hippocampus, see M. Nibuya et al., JNeurosci 15:7539-47, 1995; B. Chen et al., Biol Psychiatry 50:260-5,2001; and may increase dendritic sprouting, see S. D. Norrholm & C. C.Ouimet, Synapse 42:151-63, 2001; R. S. Duman et al.,Neuropsychopharmacology 25:836-44, 2001. LFMS may additionallystrengthen excitatory synaptic strength in the hippocampus throughelectrophysiological mecahnisms, see M. Korte et al., J Physiol Paris90:157-64, 1996; H. Kang et al., Neuron 19:653-64, 1997. One explanationof this process suggests that reductions in neurotrophic factors,notably brain derived neurotrophic factor (BDNF), are linked to systemssuch as cAMP response element binding protein (CREB), through secondmessenger pathways such as cAMP and Ca++, see M. A. Smith et al., JNeurosci 15:1768-77, 1995; T. E. Meyer & J. F. Habener, Endocr Rev14:269-90, 1993; A. Ghosh & M. E. Greenberg, Science 268:239-47, 1995.The presence of ions such as Ca⁺⁺ in these neural signaling pathways andthe electrochemical nature of many of the synaptic receptors and ionchannels involved suggest that interaction of these systems with theelectromagnetic fields of LFMS is possible. The timing of the LFMSwaveform could be an important factor in this successful interaction.The LFMS electric field pulses are 250 microseconds in duration anddelivered at 1 kHz with alternating polarity. The timing of the LFMSelectric field pulses occurs on a timescale similar to the reactiontimes of these systems, and this may be a reason for the observation ofthe observed effects at such low field strengths. LFMS, with its singlephase excitation pulses which have sub-millisecond duration, mayinteract efficiently with these signaling systems in the brain becausemany components of these systems (such as ion channels) have a responsetime on the order of 1 ms.

Antidepressant medications have been hypothesized to increase monoaminesat central synapses. This, in turn, influences intracellular secondmessenger systems, which activates neurogenesis and dendritic sproutingin the hippocampus, and leads to improved neuronal function. It has beenproposed that the antidepressant effects of magnetic stimulation of thecortex act through presynaptic inputs to the hippocampus and participatein this process, see M. Popoli Metal., Bipolar Disord 4:166-82, 2002.The time course of patient response to antidepressant treatments is onthe order of weeks, and may be indicative of the time required for thisneurogenesis, see H. K. Manji HK et al., Biol Psychiatry 53:707-42,2003. This model of the antidepressant effects of magnetic stimulationof the cortex, suggesting that primary effects occur with stimulation inthe cortex but have long term secondary effects in the hippocampus, mayapply to LFMS.

A number of proposed mechanisms for depression have been explored usingboth cognitive and neurobiological models. Cognitive models have beenstudied with functional imaging techniques that examine metabolic andhemodynamic changes in resting brain state. These types of studies usingPET and MR show a pattern of cortical hypometabolism in dorsalprefrontal cortical regions and of hypermetabolism in paralimbic andventral cortical regions, see C. E. Bearden et al., Bipolar Disord3:106-50, 2001 (in particular pages 151-53); H. S. Mayberg, Semin ClinNeuropsychiatry 7:255-68, 2002; R. T. Dunn et al., Biol Psychiatry51:387-99, 2002; R. M. Post et al., Ann Clin Psychiatry 15:85-94, 2003.These metabolic states are reversed with successful treatment orremission of depression. One study identified pre-treatment perfusionlevels in the rostral cingulate as a possible marker of successfultreatment, see H. S. Mayberg, Br Med Bull 65:193-207, 2003 in manicdepressive disorder, while another implicated cerebellar regions in theneurobiology of bipolar depressive disorder, see T. A. Ketter et al.,Biol Psychiatry 49:97-109, 20001. In these models depression isdiscussed as a dysfunction of balanced neural circuits, with the totalinteraction between these areas being more important than changedfunction in any one area. Successful treatment or remission isaccompanied by the correction of (or compensation for) this dysfunction.LFMS may interact with these networks because LFMS may induce electricfields in the axons making up these circuits, and may modifyelectrochemical signaling mechanisms and balance within these neuralnetworks.

Depression has also been associated with abnormalities in white mattertracts in the brain. Abnormal white matter anisotropy within the frontaland temporal lobes has been observed in patients with late-lifedepression, see K. Nobuhara et al., J Neurol Neurosurg Psychiatry77:120-22, 2006. A smaller genu, the region of the corpus callosum whereinterhemispheric fibers from the frontal regions of the brain cross, hasbeen observed in depressed patients, see I. K. Lyoo et al., BiolPsychiatry 52:1134-43, 2002. In addition to general observations ofabnormalities in white matter tracts in persons with depression, suchabnormalities have in particular been found in persons with bipolardisorder. Microstructural changes and changes in anisotropy in whitematter have been found, see C. M. Adler et al., Bipolar Disorders,6:197-203, 2004; C. M. Adler et al., Am J Psychiatry, 163:322-24, 2006;J. L. Beyer et al., Neuropsychopharmacology 30:2225-29, 2005. Loss ofbundle coherence in prefrontal white matter tracts or other disruptionin network connectivity or white matter bundling may be implicated inthe symptomatology of bipolar disorder, see Adler et al., BipolarDisorders, 6:197-203, 2004. LFMS may counteract or mitigate theseadverse changes, or enhance function in compromised white matter tractsby enhancing neural signaling through electrophysiological mechanismssimilar to potentiation.

Schizophrenia and schizoaffective disorders have been associated withabnormalities in white matter tracts, cerebral circuit disconnectivity,hippocampal degeneration and with deficits of BDNF. Abnormalities in theamygdale, endtorhinal cortex, middle cerebellar peduncles, the genu andtruncus of the corpus callosum, the internal capsule and anteriorcommissure of the right hemisphere, inferior frontal white matter,anterior cingulate, caudate, insula, inferior parietal lobule, leftpostcentral gyms, right superior/middle temporal gyms, and bilateralfusiform gyms have been observed in persons with schizophrenia, see M.J. Hoptman et al., Brain Imaging 15(16):2467-70, 2004; H. E. Hulshoff etal., NeruoImage 21:27-35, 2004; G. Okugawa, et al., Neurophychobiology50:119-23, 2004; P. Kalus et al., Neuroscience Letters 375:151-56, 2005;P. Kalus et al., NeuroImage, 24:1122-29, 2005; A. M. Brickman et al., JNeuropsychiany Clin Neurosci., 18(3): 364-76, 2006; and N. Rusch & G.Spalletta, Psychiatr Danub. 1:20, 2006. LFMS could provide treatment forthe symptoms of schizophrenia and schizoaffective disorders throughdirect electromagnetic interaction with white matter tracts.

Schizophrenia has displayed neural circuit changes which could be partof its pathophysiology. Fronto-temporal connectivity changes in whitematter tracts, such as the uncinate fasciculus and cingulum bundle, havebeen observed in persons with schizotypal personality disorder, see M.Nakamura et al., Biol Psychiatry 58:468-78, 2005, and cerebraldisconnectivity has been seen in early stages of schizophrenia, see A.Federspiel et al., Neurobiol Dis. 22(3):702-9, 2006. Finally,schizophrenia shares some of the hippocampal volume reduction, see N.Kuroki et al., Biol Psychiatry, 60(1):22-31, 2006, and BDNF dysfunctioneffects, see G. Shoval & A. Weizman, Eur Neuropsychopharmacol.,15(3):319-29, 2005, that could benefit from any post-synaptic changesaffected by LFMS treatment. Treatment of schizophrenia with rTMS hasbeen studied with positive results, particularly in the abatement ofauditory hallucinations, see P. B. Fitzgerald et al., World J BiolPsychiatry, 7(2):119-22, 2006; and Y. Jin et al., Schizophr Bull.,32(3):556-61, 2006.

Anxiety disorders such as PTSD can benefit from post-synaptic changesaffected by LFMS because they display BDNF deficits, see A. V. Kalueffet al., Science, 312(5780):1598-9, 2006. PTSD and anxiety disorder havebenefited from the electromagnetic rTMS treatment, see H. Cohen et al.,Am J Psychiatry, 161(3):515-24, 2004 and may also benefit from LFMStreatment.

Drug abuse shares many of the cognitive patterns of change in regionsregulating mood, cognitive function, memory and reward that are affectedin depression, see N. D. Volkow et al., Pharmacol Ther., 108(1):3-17,2005. It shows changes in the hippocampus similar to those ofdepression, see L. Pu et al., Nat Neurosci., 9(5):605-7, 2006; and P. H.Janak et al., Alcohol Clin Exp Res. 30(2):214-21, 2006. Treatments fordrug abuse reflect this overlap with treatments for depression, and manyantidepressant medications are also used in the treatment of drug abuse.LFMS could provide a treatment for drug abuse, providing beneficialeffects that parallel these antidepressant based treatments.

Abnormalities in white matter tracts have also been associated with anumber of other disorders, including ADHD, PTSD, and substance abuse,see Teicher et al., Psychiatr Clin N Am 25:397-426, 2002. For example,increased curvature in the genu of the corpus callosum and abnormalitiesin the posterior midbody and isthmus area of the corpus callosum havebeen observed in persons who abused methamphetamine, see J. S. Oh etal., Neuroscience Letters, 384:76-81, 2005. Evidence of abnormal whitematter microsctructure has also been found in patients with obsessivecompulsive disorder, see Arch Gen Psychiatry 62:782-90, 2005. The directaction of LFMS on white matter tracts could provide treatment for thesedisorders.

EXAMPLES Experiment

An experiment demonstrating the LFMS effect in the treatment ofdepression was performed in 2001 at McLean Hospital, see M. Rohan etal., Am J Psychiatry, 161(1):93-98, 2004. The study population wascomprised of participants in three studies of medications for bipolardisorder. These studies were investigating the effects of conventionaland non-conventional (omega3 fatty acid supplements) therapies on moodand brain chemistry over a period of time, and involved LFMS MRI scansand clinical interviews on a monthly basis. At the start of thesestudies the beneficial effects of LFMS were not known, and the LFMS MRIscan was an experimental MRI scan used to measure chemicalconcentration. Subjects had a diagnosis of Bipolar I or II Disorder andwere between the ages of 18 and 65. They were either currently on acourse of medication including lithium, Depakote, and otheranticonvulsants, or were medication free at the start of the study.Subjects who were given anxiolytic medication during the scan sessionsor who were taking medication in addition to those listed above were notconsidered in this study. Only mood improvement data from first visitswas used to prevent confounds due to medication changes.

The “Brief Affect Scale” (BAS) measures change in immediate mood stateon a 7-point scale and was administered to all subjects immediatelybefore and after the MR scanning session. These numerically rankedresponses were grouped into the ordinal categories of “improved” (3 to1), “same” (0) and “worse” (−1 to −3) for statistical treatment.

Studies were conducted at the McLean Hospital Brain Imaging Center.Scanning was performed on a 1.5T MRI scanner. Subjects with bipolardisorder who received LFMS MRI scans received 20 minutes of LFMSsequences along with 30 minutes of anatomic MR scans at each visit. TheLFMS sequence was an Echo-Planar scan that is described below. Somesubjects with bipolar disorder were treated with a sham LFMS MRI scan inorder to provide an experimental control. The sham MRI scan wasidentical to original exam, except that the LFMS sequence was replacedwith a three-dimensioned spoiled gradient echo scan. Additionally, agroup of healthy comparison subjects were given LFMS MRI scans with thesame protocol, as a second experimental control group.

Ordered logistic regression modeling methods were used to examine thedifferences in BAS scores among the study groups. Data were summarizedas means (±SD) or by means with 95% confidence intervals (95% CI). Twosided significance tests, requiring p<0.05 for statistical significance,were employed.

Twenty-three of 30 subjects with Bipolar Disorder reported improvementin mood of at least 1 point on the BAS scale after LFMS treatment. “Nochange” was reported by 6 subjects, and a worsening of mood was reportedby 1 subject. The mean BAS score for bipolar subjects receiving LFMS was0.87±0.68. In the subgroup of unmedicated bipolar LFMS subjects, 11 of11 subjects reported improvement in mood (mean BAS score=1.18±0.41),compared to reports of improvement by 12 of 19 subjects with bipolardisorder in the subgroup taking mood stabilizing medication (mean BASscore=0.68±0.75).

Three of 10 subjects with Bipolar Disorder who received sham treatmentreported improvement in mood after the exam, with 2 reports of worseningin mood. The mean BAS score for bipolar subjects receiving shamtreatment was 0.30±1.06.

Four of 14 healthy subjects reported improvement in mood after an LFMStreatment, with no reports of worsening. The mean BAS score for healthysubjects receiving LFMS treatment was 0.29±0.47. Table A summarizesthese BAS improvement scores.

Ordinal BAS ratings were compared between bipolar subjects who receivedLFMS treatment (N=30, mean BAS=0.87±0.68) vs. those receiving shamtreatment (N=10, mean BAS=0.30±1.06) using ordered logistic regressionmethods. This difference was statistically significant (z=2.63,p=0.009). The higher BAS scores in the LFMS subjects indicate greaterperceived mood improvement in this group compared to the bipolar shamLFMS group.

Ordinal BAS ratings were compared between unmedicated bipolar LFMSsubjects (N=11, mean BAS improvement 1.18±0.41) and medicated bipolarLFMS subjects scans (N=19, mean BAS=0.68±0.75). This difference wasstatistically significant (z=2.02, p=0.044).

Ordinal BAS ratings were also compared between bipolar LFMS subjects(N=30, mean BAS=0.87±0.68) and healthy subjects who received LFMS (N=14,mean BAS=0.29±0.47). This difference was also statistically significant(z=2.61, p=0.009). The contrast between bipolar sham LFMS subjects andhealthy LFMS subjects was not significant (z=0.29, p=0.77). A summary ofthese results is listed in FIGS. 4 and 5. FIG. 4 shows the results ofthe Brief Affect Scale assessment of mood in all subjects after LFMS orsham treatment. FIG. 5 shows the statistical significance of thecontrast between mood improvement in the different groups of subjects.

We found significant improvement of mood in depressed subjects withbipolar disorder after LFMS treatment. This improvement was absent inbipolar subjects who received sham LFMS treatment, and was also absentin healthy subjects who received LFMS treatment. A greater effect wasevident in medication-free subjects.

The treatments were administered using a General Electric 1.5T Signa MRIscanner. After optional water suppression, slice selective excitation,and a spatial phase encoding pulse, the device applied a train of 512trapezoidal alternating-polarity magnetic field pulses. These pulseswere about one millisecond long, with ramp times of 128 microseconds and768 microsecond plateau times. During the plateau of each pulse, thegradient was 0.33 G/cm, and the maximum magnetic field in the cortex wasabout 5 G. The entire train of 512 pulses was repeated every 2 seconds,six hundred times, for a total treatment time of 20 minutes. FIG. 2 is adiagram of the magnetic field pulse train. The ‘X’ gradient coil in themagnetic resonance scanner, having an approximate diameter of about 90cm (36 in.), was used to apply this sequence, orienting the gradient inthe right-left direction for the supine subjects. The gradient of thez-component of the magnetic field from this coil in the x-direction isuniform in both magnitude and direction over a subject's brain to withinabout 5%.

The magnetic field induced an electric field in the brains of thesubjects. This electric field was oriented from front to back, from thesubject's perspective. The induced electric field consisted of 256microsecond monophasic square pulses, where each pulse has a singlepolarity and an amplitude of approximately 0.7 V/m. A diagram of thiselectric field waveform is shown in FIG. 3.

To achieve the same electric field with a smaller coil, Maxwell'sequations show that a higher magnetic field may be required. Using acoil with a similar shape but smaller diameter, e.g., a “head-sized” 35cm (14 in.) coil instead of a 36-inch “whole-body” gradient coil thatwas in the MRI system, to induce a similar same electric field magnitudewould employ a magnetic field that reaches approximately 50 G in thehead. The magnetic field used to induce such an electric field can havea vector component with a gradient that is slightly less uniform invalue and direction, varying by about 10% over the cranial volume. Inaddition, a higher magnetic field, e.g., 100 G, can be used with asmaller coil that provides a vector component with a substantiallyuniform gradient over only a region, e.g. 8 cm³, of the brain.

Comparative Example

rTMS employs electric fields on the order of 500 V/m in the cortex, morethan sufficient to cause neural depolarization, and fields on the orderof 50V/m in subcortical structures, see M. Nadeem et al., IEEE TransBiomed Eng, 50:900-7, 2003. It uses a bi-phasic waveform that reversessign during each pulse. The electric field direction for rTMS has acircular pattern similar to a projection of the magnetic loops that areits source. LFMS, however, has electric fields that are relatively weakin comparison to other stimulation techniques (<1 V/m), not enough todepolarize a neuron in general, but that penetrate uniformly through allstructures. LFMS uses a monophasic waveform that does not reverse signduring the pulse. Finally, the LFMS field observed to produce thiseffect has a uniform direction rather than the circular direction ofrTMS.

One example of an rTMS technique uses a figure-8 surface coil with loopsthat are 4 cm in diameter (Cadwell, Kennewick, Wash.). This coil isplaced next to the scalp, and is usually positioned to direct themagnetic field at the prefrontal cortex of the brain, see, e.g., Georgeet al., The Journal of Neuropsychiatry and Clinical Neurosciences,8:373, 1996. An electric current is run through the magnetic coil togenerate a magnetic field, specifically a sequence of single-cyclesinusoidal pulses where each pulse has a frequency of approximately 1800Hz (or about 560 microseconds per pulse). These pulses are delivered ata repetition rate of 1 Hz (i.e., one single-cycle sinusoidal pulse every1 second), see, e.g., George et al, Biological Psychiatry, 48:962, 2000;Eschweiler et al, Psychiatry Research: Neuroimaging Section, 99:161,2000. This waveform is shown in FIG. 6. As the repetition period is muchlonger than the time span on the time axis, only one single-cyclesinusoidal pulse appears in FIG. 6.

The magnetic field generated by the FIG. 6 waveform is shown in FIG. 7.The field reaches its maximum strength of approximately 10,000 G at theface of the coil. The strength of this magnetic field decreases rapidlyas the distance from the coil increases, to about less than 1 G at about6 cm to 8 cm, see, e.g., Cohen et al, Electroencephalography andClinical Neurophysiology, 75:350, 1990.

FIG. 8 shows the electric field waveform induced in the subject's brainby the magnetic field shown in FIG. 7. This waveform consists of aseries of 560-microsecond single-cycle cosine pulses that repeat every 1Hz.

FIG. 9 shows the contour plot and FIG. 10 shows the three-dimensionalplot of the electric field induced in free space by the magnetic fieldshown in FIG. 2. The electric field is approximately 120 V/m at the faceof the coil, and falls to about 0.02 V/m on the side of the headopposite the coil. The contours of this rapidly diminishing electricfield reflect the shape of the figure-8 surface coil with 4 cm diameterloops, tilted at 45°, and placed 6.7 cm vertically and horizontally froma position equivalent to the center of the head: the electric fieldforms roughly circular loops.

FIG. 11 shows a table comparing parameters for an exemplary rTMSprotocol to parameters for an exemplary LFMS protocol. As shown, LFMSuses a lower peak magnetic, a lower peak electric field, a lowerelectric field pulse duration than rTMS, and a higher field pulse rate.This LFMS technique also uses monophasic pulses of alternating signcompared to the use of biphasic pulses of the same sign in rTMS. Theelectric field direction in the LFMS technique is unidirectional, whilethe electric field direction in rTMS is circular.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A system comprising: a magnetic coil configured to produce a magneticfield in response to an electrical signal; and a waveform generatorprogrammed to produce the electrical signal such that the magnetic fieldcomprises a time-varying magnetic field with a maximum strength of lessthan about 50 G, wherein the magnetic field induces an electric field inair comprising a series of electric field pulses, and wherein theelectric field pulses are monophasic and separated by periods ofsubstantially no electric field.
 2. The system of claim 1, wherein themaximum strength of the magnetic field is less than about 10 G.
 3. Thesystem of claim 1, wherein the electric field pulses have amplitude lessthan about 10V/m.
 4. The system of claim 3, wherein the duration of eachelectric field pulse is less than or equal to about 10 milliseconds. 5.The system of claim 1, wherein the duration of each electric field pulseis less than or equal to about 1 millisecond.
 6. The system of claim 1,wherein a spatial gradient of the magnetic field is substantiallyuniform.
 7. The system of claim 6, wherein the magnetic coil isconfigured to generate the magnetic field over a region of interest. 8.The system of claim 1, wherein the magnetic coil is configured toreceive at least a portion of a subject's head within the coil.
 9. Awaveform generator programmed to produce an electrical signal fordelivery to a magnetic coil such that the magnetic coil produces atime-varying sequence of magnetic field pulses in response to theelectrical signal, wherein each of the magnetic field pulses isunidirectional and has a substantially uniform spatial gradient.
 10. Thewaveform generator of claim 9, wherein the maximum strength of themagnetic field pulses is less than about 500 G.
 11. The waveformgenerator of claim 9, wherein the maximum strength of the magnetic fieldpulses is less than about 50 G.
 12. The waveform generator of claim 9,wherein the time varying sequence of magnetic field pulses comprisespulses each having duration less than about 10 milliseconds and beingtrapezoidal shaped with a plateau between two magnetic field ramps. 13.A waveform generator programmed to produce an electrical signal fordelivery to a magnetic coil, the magnetic coil producing a magneticfield in response to the electrical signal, the magnetic fieldcomprising a time-varying magnetic field, wherein the magnetic fieldinduces an electric field in air comprising a series of electric fieldpulses, wherein the series of electric field pulses has a frequency ofat least about 100 Hz, and wherein each electric field pulse has asingle polarity and the pulses are separated by periods of substantiallyno electric field.
 14. The waveform generator of claim 13, wherein themaximum strength of the magnetic field is less than about 500 G.
 15. Thewaveform generator of claim 13, wherein the maximum strength of themagnetic field is less than about 50 G.
 16. The waveform generator ofclaim 13, wherein the electric field pulses have amplitude less thanabout 10V/m.
 17. The waveform generator of claim 13, wherein theelectric field pulses have amplitude less than about 5V/m.
 18. Thewaveform generator of claim 13, wherein the time varying magnetic fieldcomprises a sequence of magnetic field pulses each having duration lessthan about 10 milliseconds and being trapezoidal shaped with a plateaubetween two magnetic field ramps.
 19. The waveform generator of claim18, wherein each electric field pulse is generated during field ramps oftwo succeeding magnetic field pulses.
 20. The waveform generator ofclaim 18, wherein the periods of substantially no electric fieldcorrespond to the plateaus of the trapezoidal shaped magnetic fieldpulses.
 21. The waveform generator of claim 13, wherein the frequency ofthe series of the electric field pulses is about 1 kHz.
 22. The waveformgenerator of claim 21, wherein the series of electric field pulsescomprises multiple pulse trains, wherein each pulse train comprisesabout 512 pulses and lasts about a half second and wherein successivepulse trains are separated by about one and a half seconds.
 23. Awaveform generator programmed to produce an electrical signal such thata magnetic field is produced by a magnetic coil in response to theelectrical signal, the magnetic field comprising a time-varying magneticfield, wherein the magnetic field induces an electric field in aircomprising a series of electric field pulses, wherein the electric fieldis substantially unidirectional over at least a region of the brain, andwherein each electric field pulse has a single polarity and the electricfield pulses are separated by periods of substantially no electricfield.
 24. The waveform generator of claim 23, wherein the maximumstrength of the magnetic field is less than about 500 G.
 25. Thewaveform generator of claim 23, wherein the maximum strength of themagnetic field is less than about 50 G.
 26. The waveform generator ofclaim 25, wherein the electric field pulses have amplitude less thanabout 10V/m.
 27. The waveform generator of claim 23, wherein theelectric field pulses have amplitude less than about 5V/m.
 28. Thewaveform generator of claim 27, wherein the duration of each electricfield pulse is less than or equal to about 10 milliseconds.
 29. Thewaveform generator of claim 23, wherein the duration of each electricfield pulse is less than or equal to about 1 millisecond.
 30. Thewaveform generator of claim 23, wherein the frequency of the series ofthe electric field pulses is at least about 100 Hz.